Maternal substance abuse is a significant public health problem with wide-ranging, negative consequences. Substance use in pregnancy is prevalent, particularly among disadvantaged groups, and is often associated with sporadic, late, or no prenatal care, precluding identification, referral and treatment prior to hospital delivery. Infants born to substance-using mothers are often premature or at low birth weights and admitted to the neonatal intensive care unit (NICU), making this an important setting for initial intervention. Maternal substance use is associated with inadequate childcare and neglect which can have especially devastating consequences for fragile NICU infants. Further, without intervention, many of these mothers will become pregnant again within a short period of time, increasing burden on themselves, their families and society. Prolonged hospitalization in the NICU provides a unique opportunity to intervene with distressed young mothers in crisis, who may have higher levels of motivation to seek help for high-risk behaviors (substance use) and adopt healthy ones (family planning; disease prevention). We predict that a novel, empirically-grounded, hospital-tailored intervention combined with gynecological follow-up in the NICU (i.e., physicians providing reproductive health and HIV/HCV counseling) will increase treatment initiation, reduce substance use, prevent future substance-exposed pregnancies (SEPs), and reduce risk of HIV and HCV. As NICU infants are disproportionately born to disadvantaged, minority families, intervention with this population is critical for reducing economic and racial health disparities. A randomized, controlled group design will be used to allow a rigorous assessment of the feasibility and efficacy of an adaptive, brief, hospital-delivered intervention comprising a novel combination of evidence- based treatments (motivational interviewing [MI] and acceptance and commitment therapy [ACT]) targeting substance abuse treatment initiation and reduced risk of SEPs for mothers with a high-risk, NICU infant. Mothers (N = 64) will be randomized to either: MI-ACT or Conventional Care (CC). MI-ACT treatment intensity (1, 2, or 3 sessions) will vary based upon participant response (i.e., treatment initiation), per the adaptive intervention strategy. An efficacy assessment at 8 weeks post-baseline will assess treatment entry, substance use, and SEP/HIV/HCV risk. MI-ACT treatment mechanisms (i.e., motivation for change; psychological flexibility) will also be investigated. At the 6-month follow-up, broader maternal and infant benefit will be assessed (e.g., child custody; acute care pediatric visits; re-hospitalization). An innovative Bayesian analysis is planned to determine potential benefit of the MI-ACT intervention, which proactively addresses the inevitable problem of power when conducting initial efficacy trials of new interventions in relatively smaller samples. Effective bref, hospital-based interventions targeting substance-using mothers of infants at high medical risk could result in substantial decreases in adverse health and social effects and the large associated costs.